Mutational analysis of the tau gene in progressive supranuclear palsy

Objective: To identify genetic mutations in the coding regions and the spli ce-donor sites of the tau gene on chromosome 17q in individuals with progre ssive supranuclear palsy (PSP). Background: Several studies provide evidenc e for linkage disequilibrium between a PSP disease gene and allelic variant s of the tau gene. However, a causative mutation has not been identified. M ethods: We designed a study to search for genetic mutations in 15 coding re gions of the tau gene including the splice-donor sites in 22 patients with PSP by comparing the mobility shifts on single-strand conformation analysis with those of age-matched controls. Fragments with altered migration were sequenced directly and compared for differences in nucleotide composition. Restriction enzyme digests were used to confirm single base-pair substituti ons. Results: Significant differences in mobility shifts were found in exon s 1, 4A, and 8 between affected individuals and age-matched controls. All i ndividuals with PSP had a common extended haplotype characterized by a homo zygous polymorphism in the 5' splice site untranslated region of exon 1, tw o missense mutations in exon 4A ((Asp)285(Asn), (Ala)289(Val)), and a nonse nse mutation in the 5' splice site of exon 8. Conclusions: This study demon strates that 22 unrelated progressive supranuclear palsy (PSP) patients hav e four identical sequence variants within the tau gene that are not present in 24 age-matched controls. Although the functional significance of these results on tau protein expression is unknown, the presence of this "suscept ibility" haplotype in individuals may place them at risk for developing PSP .